Case report: Pulse cyclophosphamide for treatment of multi-agent-refractory hepatic graft-versus-host disease.

Graft-versus-host disease (GVHD) is a common complication in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized as either acute or chronic based on symptomatology and histopathological findings. Despite advancements in disease-targeting therapeutics, steroid-refractory GVHD remains a significant contributor to mortality in HSCT recipients, highlighting the gaps in our understanding of its pathophysiology and treatment strategies. We present the case of a 46-year-old woman diagnosed with acute undifferentiated leukemia, who exhibited persistently elevated levels of serum total bilirubin (T.Bili), alkaline phosphatase (ALP), and liver function tests (LFTs) beginning on [day +201] post-haploidentical peripheral blood stem cell (PBSC) transplantation. The patient received fludarabine/total body irradiation (Flu/TBI) as a myeloablative conditioning regimen and post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as GVHD prophylaxis. A liver biopsy confirmed the diagnosis of GVHD, while other possible etiologies were excluded by corresponding tests. Initial treatment with prednisone and tacrolimus, and the later addition of ruxolitinib, all showed poor response indicated by worsening T.Bili, ALP, and LFTs at the same time. Based on a multidisciplinary comprehensive assessment, we decided to administer 1,000 mg/m2 (1,600 mg) of cyclophosphamide ("pulse Cy"), which resulted in a dramatic improvement in T.Bili and transaminases starting from the very next day. A durable response to pulse cyclophosphamide was observed, as all indicators normalized ("complete response") within 55 days without relapses. The patient remains in good health with no recurrence of hepatic GVHD. To our knowledge, this is the first case in which Grade IV hepatic GVHD, refractory to multiple agents including steroids, tacrolimus, and ruxolitinib, demonstrated a complete response to pulse cyclophosphamide. The success highlights the potential therapeutic role of cyclophosphamide, a potent and cost-effective chemotherapy agent, in treating multi-agent-refractory GVHD. Large-scale clinical trials are warranted to validate its efficacy in this setting.

Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Treatment Patterns for Distal Radius Fractures Before and After Appropriate Use Criteria Adoption.

BACKGROUND: The purpose of this study was to determine agreement with the American Academy of Orthopaedic Surgery Appropriate Use Criteria (AUC) for distal radius fractures (DRFs), before and after their adoption, and secondarily determine predictors of operative management. METHODS: A single-institution retrospective cohort study comparing patients treated either nonoperatively (115 patients) or operatively (767 patients) for DRFs between May 1, 2008, and May 1, 2018, by 8 hand surgeons was performed. Data included demographics, injury characteristics, DRF radiographic measurements, treatment rendered, and their appropriateness according to the AUC. Statistical testing used the Fisher and χ2 tests, t test, and multiple variable logistic regression, with a significance level of .05. RESULTS: Overall, there was a significant increase in AUC agreement for operatively treated DRFs (82.7%-89.3%, P = .01), but no difference in agreement for nonoperatively treated DRFs (12.5%-10.7%, P = .77). Age <80 years, AO classes other than B, intra-articular displacement >1 mm, radial inclination <18°, high-energy mechanism of injury, and greater than 1 week to treatment were independent predictors of operative treatment. The area under the curve for the validated regression model using the aforementioned predictors was 0.82. CONCLUSION: Agreement with AUC for DRFs increased after its adoption for operatively treated, but not for nonoperatively treated, fractures. In addition, a predictive model for operative treatment was developed and validated. Future studies may benefit from further model refinement and testing in other patient cohorts.

Outcomes following Distal Radius Fractures with Preexisting Ulnocarpal Abutment.

Background Due to the commonality of distal radius fractures (DRFs), the potential impact of ulnocarpal abutment (UA) on patient outcomes is significant, whether it developed after or prior to injury. It is, therefore, important to consider whether preexisting UA has any impact on outcomes after an acute DRF. Questions/Purpose The aims of this study were to determine if differences were present in (1) pain at final follow-up, (2) complications, and (3) unintended operations in patients with DRFs and either without or with preexisting radiographic UA. Methods A single institution retrospective cohort study comparing patients treated either nonoperatively (43 patients) or operatively (473 patients) for DRFs between 5/1/2008 to 5/1/2018 was performed. Data included demographics, prior wrist pain or surgery, ulnar variance, select treatment data, and presence of pain, complication, or unintended operation by final follow-up. Statistical testing used Fisher's exact test and chi-squared test, with a significance level of 0.05. Results The prevalence of preexisting UA was 14.0 and 15.6% in the nonoperatively- and operatively treated groups, respectively. In nonoperatively treated patients without or with UA, no differences in pain (37.8 vs. 33.3%, p = 1.00) or complications were seen (13.5 vs. 50.0%, p = 0.07). A higher unintended operation rate for nonoperatively treated DRFs with UA, compared with those without, UA was seen (5.4 vs. 50.0%, p = 0.01). No differences in pain, complications, or unintended operations were seen between those without and with UA in the operatively treated group. Conclusion Preexisting UA is not associated with pain, complications, or unintended operations after operative treatment of DRFs. Prospective studies further evaluating outcomes in nonoperatively treated DRFs with UA may be beneficial.

30- and 90-Day Unplanned Readmission Rates, Causes, and Risk Factors After Cervical Fusion: A Single-Institution Analysis.

STUDY DESIGN: Retrospective cohort study OBJECTIVE.: To study 30- and 90-day readmission rates, causes, and risk factors after anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF). SUMMARY OF BACKGROUND DATA: Existing data on readmission after cervical fusion is majorly derived from national databases. Given their inherent limitations in accuracy, follow-up available, and missing data, we intend to add to literature from our institutional analysis. METHODS: Patients who underwent ACDF and PCF for degenerative cervical pathology in 2013 and 2014 were identified for the study. Comprehensive chart review was performed to record demographics and clinical patient profile. Hospital readmission within 30 and 90 days was identified, and the causes and management were recorded. Binary logistic regression analysis was done to study risk factors for readmission. ACDF and PCF were studied separately. RESULTS: Our analysis included a total of 549 patients, stratified as 389 ACDFs and 160 PCFs. The 30- and 90-day unplanned readmission rate was 5.1% and 7.7% after ACDF. These rates were 11.2% and 16.9% after PCF. The most common cause of readmission was systemic infection and sepsis after ACDF and PCF (31.4% and 25.8% of readmitted, respectively), followed by pulmonary complications after ACDF (14.3% of readmitted) and wound complications after PCF (19.4% of readmitted). Predictors of readmission after ACDF included heart failure, history of malignancy, history of deep vein thrombosis/pulmonary embolism, and any intraoperative complication. In the PCF cohort, history of ischemic heart disease, increasing number of fusion levels and longer length of stay were independently predictive. CONCLUSION: The rates, causes, and risk factors of readmission after ACDF and PCF have been identified. There is variation in published data regarding the incidence and risk factors for readmission after cervical fusion; however, majority of readmissions occur due to medical complications and systemic infection. LEVEL OF EVIDENCE: 3.

Preferred Place of Death for Patients With Incurable Cancer and Their Family Caregivers in Egypt.

BACKGROUND:: Little is known about the place of death of patients with cancer in Eastern Mediterranean countries including Egypt, where palliative care is underdeveloped. Identifying the preferred place of death (PPoD) is important for the development of appropriate palliative care models in these countries. OBJECTIVES:: To know the PPoD of Egyptian patients with incurable cancer and their family caregivers (FCGs) and to determine the factors that may impact their preferences. METHODS:: An observational cross-sectional study that included 301 dyads of patients with incurable cancer and one of their FCGs. A questionnaire was designed to collect data about the characteristics of patients and FCGs as well as their preferences. RESULTS:: The majority of dyads (272/301, 90.4%) answered the PPoD question. Home was the PPoD in 93% of patients and 90.1% of FCGs ( P = .218). The congruence between patients' and FCGs' PPoD was 92.7% (κ = 0.526). In multivariate analysis, poorer performance status (Eastern Cooperative Oncology Group 3 or 4) and full employment of FCGs associated significantly with patients' preference to die in hospital (odds ratio [OR] = 3.015 [95% confidence interval [CI]: 1.004-9.054], P = .049 and OR = 4.402 [95% CI: 1.561-12.417], P = .005, respectively), while poorer performance status and nonreferral to the palliative medicine unit were associated with FCGs' preference of hospital death (OR = 2.705 [95% CI: 1.105-6.626], P = .029 and OR = 2.537 [95% CI: 1.082-5.948], P = .032, respectively). CONCLUSIONS:: The results of the current study suggest that home is the PPoD for the vast majority of Egyptian patients with incurable cancer and their FCGs. Palliative care interventions that promote home death of patients with incurable cancer are needed in Egypt.

S-Palmitoylation Sorts Membrane Cargo for Anterograde Transport in the Golgi.

While retrograde cargo selection in the Golgi is known to depend on specific signals, it is unknown whether anterograde cargo is sorted, and anterograde signals have not been identified. We suggest here that S-palmitoylation of anterograde cargo at the Golgi membrane interface is an anterograde signal and that it results in concentration in curved regions at the Golgi rims by simple physical chemistry. The rate of transport across the Golgi of two S-palmitoylated membrane proteins is controlled by S-palmitoylation. The bulk of S-palmitoylated proteins in the Golgi behave analogously, as revealed by click chemistry-based fluorescence and electron microscopy. These palmitoylated cargos concentrate in the most highly curved regions of the Golgi membranes, including the fenestrated perimeters of cisternae and associated vesicles. A palmitoylated transmembrane domain behaves similarly in model systems.

The Use of the Chuang's Prognostic Scale to Predict the Survival of Metastatic Colorectal Cancer Patients Receiving Palliative Systemic Anticancer Therapy.

BACKGROUND: With the increasing number of agents active against cancer, advanced cancer patients including metastatic colorectal cancer (mCRC) patients may continue receiving palliative systemic anticancer therapy (PSAT) near the end-of-life. Validated palliative prognostic models, such as the Chuang's prognostic scale (CPS), may be helpful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT. AIM: To test the ability of the CPS to predict the survival of mCRC under treatment with PSAT. METHODS: CPS was prospectively assessed in 36 mCRC patients who were receiving PSAT. The scale is based on eight items: ascites, edema, cognitive impairment, liver and lung metastases, performance status, tiredness, and weight loss. The total CPS score ranges from 0 to 8.5 with the higher score indicating worse prognosis. RESULTS: Patients were divided into two groups using a CPS cutoff score of 5, Group 1 with a CPS score ≤5 and Group 2 with a CPS score >5. Using this cutoff value, 3-month mortality was predicted with a positive predictive value of 71%, a negative predictive value of 77%, a sensitivity of 67%, a specificity of 81% and an overall accuracy of 75%. Group 1 patients had a longer median survival of 149 days (95% confidence interval [CI]: 82-216) in comparison to Group 2 patients who had a median survival of 61 days (95% CI: 35-87). The difference in survival was statistically significant (P = 0.01). CONCLUSION: CPS may be useful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT.

Hypofractionation versus conventional fractionation radiotherapy after conservative treatment of breast cancer: early skin reactions and cosmetic results.

PURPOSE: To compare in a prospective trial the acute skin reaction and late cosmetic effects of normal fractionation versus hypofractionation radiotherapy after breast conserving surgery. PATIENTS AND METHODS: Thirty patients with T 1-2N0M0 breast cancer who underwent breast conserving surgery (BCS) were included in the study. Half of the patients received whole breast irradiation, consisting of 50 Gy/25f/5w+boost 10Gy/5f/1w to tumor bed (group A). The other half received 42.5Gy/16f/22 days (group B). The two groups were comparable otherwise. Early skin reaction and late cosmetic results were graded according to RTOG guidelines. RESULTS: The study showed no statistical significant difference between the two treatment groups as regards acute skin reactions and cosmetic appearance. However, the maximum skin reaction occurred 2 weeks earlier for patients within group B (3rd week) compared to group A (5th week). Apart from breast volume, there was no significant correlation between any of the patients or tumor factors and the incidence of acute skin reactions in either group of patients. Patients with large breast volume >1100cc had a higher rate and a longer duration of maximum skin reaction in group A (4 weeks versus 2 weeks in patients with small breast volume